Project Summary/Abstract Major Depressive Disorder (MDD) is a prevalent and debilitating illness. Risk for MDD is transmitted across familial generations; in fact, investigators have consistently documented a three- to six-fold increase in the risk for developing MDD in offspring of depressed parents. Although researchers have begun to examine mechanisms underlying this heightened familial risk for MDD, we still know little about the origins and the developmental course of abnormalities documented in children of depressed parents or about the specific parental behaviors that contribute to risk for psychopathology in offspring. The interactions between caregiver and infant represent the primary experience-dependent feature of the child?s early life. Given the plasticity of the infant brain, problematic or suboptimal caregiving during infancy is posited to create a developmental cascade, affecting normative brain trajectories, resulting in altered functioning in subsequent developmental stages, and increasing risk for psychopathology. We currently have little knowledge, however, about the effects of specific caregiving behaviors that characterize depressed parents on infant neural structure and function, and on infant stress reactivity and regulation, as measured by endocrine responses. In addressing this gap, we propose to adopt an RDoC framework to develop and examine a novel assessment of the quality of caregiving in early life and its relation to infant neural and endocrine systems implicated in the development of MDD. Specifically, two constructs from the RDoC Social Processes Domain, which have been linked to maternal depressive symptoms, are of interest: Perception and Understanding of Others; and Social Communication. We propose to recruit mother?infant dyads selected to vary in caregiver social processes. We will conduct a multi-method assessment that includes self-report, task-based, and laboratory-based measures of caregiver behaviors related to these two RDoC constructs. We will also conduct structural and functional MRI scans in infants, and will collect cortisol from infants during a laboratory-based social stressor. Thus, we will be able, for the first time, to integrate comprehensive measures of caregiver social processes, infant neural structure and function, and infant endocrine function. We predict that quality of caregiver empathy and communication will be associated with specific neural and endocrine characteristics in infants. Integrating assessments of maternal caregiving behaviors with infant neural and endocrine characteristics within an RDoC framework is critical for delineating the heterogeneity documented in the outcomes of offspring of depressed mothers. Findings from this project promise to yield specific insights concerning mechanisms involved in the early intergenerational transmission of risk for psychopathology and facilitate the development of more effective approaches to prevention and intervention in young children at risk for disorder.